Compositions containing pyrazolylpyridinium salts and method of administration



United States Patent s 341 413 COMPOSITIONS coNiAmING PYRAZOLYLPYRI-DINIUM SALTS AND METHOD OF ADMINIS- TRATION Edward Charles Tocus, WestNyack, N. and Victor N.J., assiguors to American Cy- Maine No Drawing.Filed June 15, 1965,

20 Claims. (Cl. 167-65) This invention relates to new compositions ofmatter. More particularly, it relates to compositions containing as anactive ingredient a pyrazolylpyridinium salt and method of administeringthe same.

The active components of the new compositions may be illustrated by thefollowing formula:

wherein R is selected from the group consisting of hydrogen, lower alkyland cyclopropyl; R is selected from the group consisting of hydrogen andlower alkyl; R is selected from the group consisting of lower alkyl,lower alkenyl, cinnamyl, cyclopropyl-methyl and lower alkoxy (lower)alkyl; R is selected from the group consisting of hydrogen and loweralkyl and X is a pharmaceutically acceptable anion such as, for example,chloride, bromide or iodide. Illustrations of compounds of the presentcompositions and their activity are shown in table hereinafter.

The above-described compounds which are active components of thecompositions of this invention may be prepared by a three-stagesequence. Thus, an ester of a pyridine-4-canboxylic acid is reacted witha methyl ketone to provide a 1-(4-pyridyl)-1,3-alkyldione; or ethylformate is reacted with a pyridyl ketone in the presence of a base suchas, for example, sodium methoxide to provide a 1--(4-pyridyl)-1,3-a1kyldione salt. The resulting dione or salt is reactedwith hydrazine hydrate or hydrazine dihydrochloride to give a 4-[3(5)-pyrazolyl]pyridine. These latter compounds are quaternized to theactive components of this invention generically described as 4-[3(5)-pyrozolyl]-pyridiniurn salts, with a lower alkyl, lower alkenyl,cinnamyl, cyclopropylmethyl, or lower alkwherein R, R R R and X are ashereinbefore defined and A is a lower alkyl group. The preparation ofthe active ingredients of the compositions of this invention will bedescribed in greater detail in conjunction with the exampleshereinafter.

The active components of the compositions of this invention have beenhound, in standard laboratory measurements using chicks andalloxan-diabetic mice, to tbe orally active hypoglycemic agents. Theprocedure used to measure blood sugar-lowering properties of the activeingredients of the compositions of this invention are as follows:

(A) Not less than two Hall Cross cockerels, 18-20 days of age, weighing120-200 grams are fasted 18 hours before oral administration of eachtest compound. For administration the test compound is suspended in 0.5%aqueous carboxymethylcellulose solution such that one milliliter ofsuspension per 100 grams of chick contains the intended dose. Two hoursafter drug administration, blood samples are obtained from the wingveins and analyzed for blood glucose concentrations by means of aTechnicon Auto Analyzer using the method of W. S. Hoffman, J. Biol.Chem. 120, 51 (1937). Appropriate standards and controlsare tested atthe same time for comparison. An average reduction of blood glucoseconcentration greater than 12% is considered hypoglycemic.

(B) Alloxan monohydrate causes selective destruction of the insulinproducing ,8-cells of the pancreas with consequent diabetes inexperimental animals Manor Farms male mice weighing 23-27 grams aregiven intravenously mg/kg. of aqueous alloxan monohydrate via the tailvein five days before oral administration of the test compound. The testcompound is suspended in 0.5% aqueous carboxymethyl-cellulose solutionsuch that 0.2 milliliter of suspension per 25 grams of mouse containsthe intended dose. Groups of not less than 5 mice for each dose are bledfrom the tail immediately prior to, and 2 to 4 hours after, oraladministration of the test compound. Blood is analyzed for glucoseconcentrations as described for chicks. Appropriate controls andstandards are tested at the same time for comparison.

Results obtained from the administration of active components of thecompositions of this invention compared to standard commercialanti-diabetic agents are shown in the table.

In general, the active ingredients of the compositions of this inventionare given at doses from 1 to 250 mg. per kilogram body weight of warmblooded animal. The following table summarizes results obtained when theactive components of the present compositions are tested as describedabove.

3 The amount of active ingredient to be given will depend upon the age,condition, Weight and other factors present in the warm-blooded animal.In the instance of a warm-blooded animal of, for example, 75 kg. thedose boxymethylcellulose, methylcellulose, polyvinylpyrrolidone, gelatinand the like. Sterile suspensions or solutions are required whereparenteral use is desired. Isotonic preparations containing suitablepreservatives are also highly may vary from 0.075 g. to 18.75 g. 5desirable for injection use.

TABLE Chicks Alloxanized Mice Avg. Percent Avg. mg. Avg. PercentDecrease Decrease From Percent Blood in Control Blood Oral Dose, ControlBlood Oral Dose, GlucoseiSE. Glucse:l:S.E.

mg./kg. Glucose After mg./kg. 0 Hour 2 Hours Control 2 Hours 4 Hours1-methyl-4[5(3)-rnethyl-3(5)-pyrazolyl]pyridinlum lodido...-.- 250 73100 4375:38 38$ 8 69 5 1-ethyl-4[5(3)-methyl-3(5)-pyrazolyl]pyridlniumiodide 200 55 100 520:1:18 29:1: 3 34:1: 61-n-butyl-4[5(3)-methy1-3(5)-pyrazolyl]pyridinium bromide. 100 18 100515:l:42 62d: 3 81d: 6 l-methyl-4[5(3)-ethyl-3(5)-pyrazolyl]pyridiniumiodide... 250 54 100 4893:33 551: 9 78:1: 61-methyl-4l3(5)-pyrazolyl]-pyridiniurn iodide 250 26 100 501i18 14:1: 850:1:14 1-n-propyl-4[5(3)-methyl-3(5)-pyrazolyl]-pyrldinium bromide..250 37 100 450:1:22 56$ 7 40:1: 81-methyl4[5(3l-isobutyl-3(5)-pyrazolyl]pyridi11ium iodide...-. 250 100444:3?) 19$ 3 1:1: 6 1-mothyl-4I5(3)-ethyl-3(5)-pyrazolyl]pyridiniumchloride 200 38 100 455:t:l8 52:1: 9 78:1: 6 1-isopropyl-4 [5 (3) -methyl-3 (5)-pyrazolyl]pyridinium chloride..- 250 9 100 438i41 15:1: 2826:1:39 1-is0propyl-4[5(3)-methyl3(5)-pyraz0lyl]pyridi11ium br0mide 25012 100 444:1:27 12d: 4 14:i:141-isobutyl-4-[5(3)-methyl-3(5)-pyrazolyl]pryidin1um bromide..- 250 43100 455:1:36 41:1:10 55i131-met-hyl-4[5(3)-methyl-3(5)-pyrazolyl]pyridinium chloride... 250 70 100460:1:18 8 74:1: 6 1-methy1-4I3(5)-pyraz0lyl]pyridinium chloride 200 22100 478:1:32 22:l:11 73:|:111-n-butyl-4[5(3)-methyl-3(5)-pyrazolyl]pyridiuium chloride. 200 37 100436:1:44 59:|:15 77:1:121-allyl-4[5(3)-n1ethyl-3(5)-pyrazolyl]pyridinium chloride 100 54 1004463:32 31:1: 9 34d: 91-methyl-4[6(3)-cyclopropyl-3(5)-pyrazolyl]pyridinium chloride 100 43100 455:1:34 12:1: 8 38*19 l-rnethyl-4l4-methyl-3(5)-pyrazolyl]-pyradium iodide 250 62 100 525:1:39 8:}: 3 14:1: 41-methallyl-4[5(3)-mcthyl-3(5)-pyrazolyl] yridinium chloride 270 88 1005S7 24 49:|:1O 58:l111,3-dimethyl-4[5(3)-methyl-3(5)-pyrazolyfipyridinium chloride. 100 70100 615:l:i2 59:1: 5 78:|: 81-einnamyl-4[5(3)-rnethyl-3(5)-pyrazolyl]pyrid1nium chloride. 250 32 1004635 22 195; 8 465:151-(3methyl-2-buten-l-yl)-4[5(3)-methyl-3(5)-pyrazolyl]pyrid1niumchloride 250 29 100 479156 60:10 93: 2-(2-buten-l-yl)-4[5(3)-methyl-3(5)-pyra diniurn chloride 250 66 100assist 50:1: 7 83:1: 4 1-(2-methoxyethyl)4[5(3)-methyl-3-(5)pyra iumchloride 250 21 100 5135:44 14:1: 6 11:1: 6i-cyclopropylmethyl-4[5(3)-methy1-3(5)-pyrazo1y bromide 200 35 100455:4:34 50:1:10 59:1: 6 0.5%Aqueous Carboxymethylcellulose Solution T01406:1:45 11:l: 3 0i 3 Standard 50 34 100 4mm 0:]: 3 --1l:l: 3B-PhenethylblguanideHyd!0cl1lor1deStandard.-... 50 53 100 452:e29 21:1:5 17 3 The active components of this invention can be used in Th termunit dosage form as used in the specification the fO m f c mp Preferablyfor Oral adminlstraand/ or claims refers to physically discrete unitssuitable ti-on in unit dosage form such as tablets, pills, capsules, asunitary dosage for warm-blooded animal subjects, each powders, granulesor oral solutions or suspensions and the unit containing a predeterminedquantity of active matelike. They may also be used as sterile parenteralsolutions rial calculated to produce the desired therapeutic effect orsuspensions. For preparing solid compositions such as in associationwith the required pharmaceutical diluent, tablets, the principal activeingredient is mixed with cOncarrier or vehicle. The specifications forthe novel unit ventional tableting ingredients such as corn starch,lactose, dosage forms of this invention are dictated by and are sucrose,sorbitol, talc, stearic acid, magnesium stcarate, directly dependent on(a) the unique characteristics of dicalcium phosphate, gums, andfractionally similar matbthe active material and the amount of bloodsugar-lowerrials as pharmaceutical diluents or carriers. The table-ts oring eifect to be achieved, and (b) the limitations inherent pills of thenovel compositions can be laminated or otherin the art of compoundingsuch an active material for wise compounded to provide a dosage formaffording the therapeutic use in warm-blooded animals as disclosed inadvantage of prolonged or delayed action or predeterdetail in thisspecification, these being features of the mined successive action ofthe enclosed medication. For present invention. Examples of suitableoral unit dosage example, the tablet or pill can comprise an innerdosage forms in accord with this invention are tablets, capsules, and anouter dosage component, the latter being in the pills, powder packets,granules, wafers, cachets, teaspoonform of an envelope over the former.The two components 55 fuls, dropperfuls, ampules, vials, segregatedmultiples of can be separated by an enteric layer which serves to resistany of the foregoing, and other forms as herein described.disintegration in the stomach and permits the inner com- The presentinvention will be described in greater deponent to pass intact into theduodenum or to be delayed tail in the examples which follow whichdescribe the prepin release. A variety of materials can be used for sucharation of 4-[3(5)-pyrazolyl]pyridinium salts and formuenteric layers orcoatings, such materials including a numlations containing the activecomponents. ber of polymeric acids or mixtures of polymeric acids withEXAMPLE 1 such materials as shellac, shellac and cetyl alcohol,cellulose acetate and the like. A particularly advantageous Preparationof1-(4-pyridyl)-1,3-pentanedi0ne i 0a '11 0 rise t rene m lei acid 0 olmer i zilfer wi t h kiio vz i'i ma t ri ai s contri uti n to She? eriteric A mlxture 137 (1 mole) of methyl lsomcotmate p ip of the coating g200 ml. of methyl ethyl ketone, l 1. of ether, and 59.4 g.

1.1 moles of sodium methoxi a The liquid forms in which the novelcomposition of the de 13 he ted mule? resent invention ma be incororated for administration Wlth Snmng on a Steam bath for 3 hours Themlxture 15 3 de a ueous solitions suftaibl flavored emulsions cooled,acidified with 100 ml. of acetic acid, and diluted h ctto e ame cocoWith 500 ml. of Water. The ether layer is separated, and W1 e 1 e sue 0ns 01 7 S s 01 the aqueous phase extracted with ether. The combined nutoil, peanut oil and the like, as Well as elixirs and similar vehicleswell known in the pharmaceutical compounding arts. Suitable dispersingor suspending agents for aqueous suspensions include synthetic andnatural gums, such as, tragacanth, acacia, alginate, dextran, sodiumcarether solution is dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure to 137 g. of red liquid The liquidgives a deep red color with ferric chloride test solution.

EXAMPLE 2 Preparation of 5-methyl-l-(4-pyridyl) -1,3-hexanedione Theabove compound is obtained as a red liquid from the reaction betweenmethyl isobutyl ketone and methyl isonicotinate under the conditionsdescribed in Example 1.

. EXAMPLE 3 Preparation of 1-cycl0pr0pyl-3- (4-pyridyl) -1,3-propanedione This compound is obtained as a red liquid from the reactionbetween methyl cyclopropyl ketone and methyl isonicotinate under theconditions described in Example 1.

EXAMPLE 4 Preparation of 1-(3-methyl-4-pyridyl)-1,3-butanedione Theabove compound is obtained as a red liquid from the reaction of acetoneand methyl 3-methylisonicotinate under the conditions described inExample 1.

EXAMPLE 5 Preparation of 1-(4-pyridyl) -],3-propanedione sodium salt Amixture of 74 g. (1 mole) of ethyl formate, 60.5 g. (0.5 mole) of methyl4-pyridyl ketone, 54 g. (1 mole) of sodium methoxide, and 900ml. ofbenzene is heated under reflux on a steam bath with stirring for 18hours. The mixture is cooled and filtered. The solid is washed withbenzene and cold methanol, and dried, leaving 65 g. of a light brownsolid, the sodium salt of the dione.

EXAMPLE 6 Preparation of Z-methyl-J-(4-pyridyl)-1,3-pr0panedione sodiumsalt The above compound is obtained as a brown solid from the reactionof ethyl formate and ethyl 4-pyridyl ketone under the conditionsdescribed in Example 5.

EXAMPLE 7 Preparation of 4- [5 (3 -ethy [-3 (5 -pyraz'lyl] pyridine To astirred solution of 300 g. of 100% hydrazine hydrate is added during 15minutes 137 g. (0.77 mole) of crude l-(4-pyridyl)-1,3-pentanedione. Thetemperature of the solution rises to 85 C. The mixture is stirred atroom temperature for 1 hour, diluted with 450 ml. of water, and storedovernight at C. The solid which separates is collected and dried, and itis twice recrystallized from acetone. The product Weighs 31 g. and iswhite crystals, melting point 116-117 C.

EXAMPLE 8 Preparation of 4- [5 (3 -isobutyl-3 (5 -pyrazolyl] pyridineThe compound, colorless crystals, melting point l56- 157 C., is preparedfrom hydrazine hydrate and 5- methyl-1-(4-pyridyl)-1,3-hexanedione underthe conditions described in Example 7.

EXAMPLE 9 Preparation of 4- [5 (3 -cyclopropy l-3 (5 -pyrazolyl]pyridine The above compound, colorless crystals, melting point 126 -127C. is prepared from hydrazine hydrate and 1-cyclopropyl-3-(4-pyridyl)-1,3 -propanedione under the conditions asdescribed Example 7.

EXAMPLE 10 Preparation 0 j 3-methyl-4-[5 (3 -inethyl-3 (5 pyrazolyl]pyridine This compound, light brown crystals, melting point 136-138 C.,is prepared from hydrazine hydrate and 61-(3-methyl-4-pyridyl)-1,3-butanedione in the manner described inExample 7.

EXAMPLE 11 Preparation of 4 [3 5 -pyrazolyl] pyridine To a stirredsolution of 7.5 g. (0.07 mole) of hydrazine dihydrochloride in ml. ofWater is added 5.0 g. (0.034 mole) of 1-(4-pyridyl)-1,3-propanedionesodium salt. After 2 hours, the solution is neutralized with sodiumhydroxide, and the solid which separates is collected.

Three recrystallizations from acetone give a colorless solid, meltingpoint 154-155 C.

EXAMPLE 12 Preparation of 4-[4-methyl-3 (5 -pyrazolyl] pyridine Theabove compound, a viscous orange liquid,

A 260 Inn RE 304 my EXAMPLE 14 Preparation ofJ-methyl-4-[5(3)-methyl-3(5)-pyrazolyl1- pyridiniam iodide The compound,off-White crystals, melting point 251- 252 C., is prepared from4-[5(3)-methyl-3 (5)-pyrazolyl] pyridine and methyl iodide as describedin Example EXAMPLE 15 Preparation of1-ethyl-4-[5(3)-methyl-3-(5)-pyrazolyl] pyridinium iodide The abovecompound, colorless crystals, melting point -176 C., is prepared from4-[5(3)-methyl-3(5)- pyrazolyl]pyridine and ethyl iodide following theprocedure of Example 13, except that the reaction is carried out for 2hours under reflux in ethanol.

EXAMPLE 16 Preparation of I-n-butyl-4-[5(3)-methyl-3(5)-pyrazolyl]pyridiniam bromide The compound, colorless crystals, melting point 211-212 C., 'is prepared from 4-[5(3)-methyl-3 (5)-pyrazolyl] pyridine andn-butyl bromide as described in Example 13, except that the reaction iscarried out for 18 hours under reflux in n-butyl alcohol.

EXAMPLE 17 Preparation of 1 -m ethyl-4- [3 (5 -pyraz0lyl] pyridiniumzodzde The compound, colorless crystals, melting point 189- 190 C., isprepared from 4-[3 (5 )-pyrazolyl] pyridine and methyl iodide asdescribed in Example 13, except that the reaction is carried out for 18hours at room temperature in methanol.

g. of colorless crystals,

7 EXAMPLE 18 Preparation of 1-n-propyl-4- (3 -methyl-3 (5 pyrazolyl]pyridiniam bromide The above compound, colorless crystals, melting point247248 C., is prepared using '4-[5(3)-methyl-3(5)- pyrazolyl]pyridineand n-propyl bromide in the procedure in Example 13, except that thereaction is carried out for 18 hours under reflux in ethanol.

EXAMPLE 19 Preparation of 1 -methyl-4-[5 (3 )-isobatyl-3 (5)-pyrazolyl]pyridiniam iodide The compound, colorless crystals, meltingpoint 206-- 207 C., is prepared from4-[5(3)-isobutyl-3(5)-pyrazolyl]pyridine and methyl iodide as describedin Example 13.

EXAMPLE 20* Preparation of 1-methyl-4-[5 (3) -ethyl-3 (5) -pyrazolyl]pyridinium chloride The compound, colorless crystals, melting point 250-251 C., is prepared from the reaction of 4-[5(3)-ethyl-3(5)-pyrazolyl]pyridine and methyl chloride as described in Example 13,except that the reaction is carried out for 18 hours in a bomb at 90 C.with excess methyl chloride as solvent.

EXAMPLE 21 Preparation of 1-isopropyl-4-[5 (3 )-methyl-3 (5pyraxolyl]pyridinium chloride The compound, colorless crystals, meltingpoint 242- 243 C., is prepared from 4-[5 (3)-methyl-3 (5 -pyrazolyl]pyridine and isopropyl chloride as described in Example 13, except thatthe reaction is carried out in a bomb for 18 hours at 80 C. with excessisopropyl chloride as solvent.

' EXAMPLE 22 Preparation of 1-isopropyl-4-[5 (3)-methyl-3 (5)-pyrazolyl]pyridiniurn bromide The above compound, colorless crystals,melting point 217218 C., is prepared from 4-[5(3)-methyl-3(5)-pyrazolyl1pyridine and isopropyl bromide following the procedure ofExample 13, except that the reaction is carried out 'for 42 hours in abomb at 160 C. with excess isopropyl bromide as solvent.

EXAMPLE 23 Preparation of 1 -isobutyl-4-[5 (3 )-methyl-3 (5 -pyrazolyl]pyridinium bromide The compound, colorless crystals, melting point 235-236 C., is prepared from 4-[5(3)-methyl-3(5)-pyrazolyl] pyridine andisobutyl bromide as described in Example 13, except that the reaction iscarried out for 18 hours under reflux in n-butyl alcohol.

EXAMPLE 24 Preparation of 1-methyl-4-[5 (3 )-methyl-3 (5 )-pyrazolyl]pyridinium chloride The compound, colorless crystals, melting point 251252 C., is prepared from 4-[5(3)-methyl-3 (5)pyrazolyl] pyridine andmethyl chloride as described in Example 13, except that the reaction iscarried out for 18 hours in a bomb at 90 C. with excess methyl chlorideas solvent.

EXAMPLE 25 Preparation of 1-methyl-4- [3 (5) -pyrazolyl] pyridiniamchloride The compound, colorless crystals, melting point 232- 233 C., isprepared from 4-[3(5)-pyrazolyl]p-yridine and methyl chloride asdescribed in Example 13, except that the reaction is carried out for 18hours in a bomb at 90 C. with excess methyl chloride as solvent.

8 EXAMPLE 26 EXAMPLE 27 Preparation of 1-allyl-4-[5 (3)-methyl-3 (5)-pyrazolyl] pyridinium chloride The compound, colorless crystals,melting point 243"- 244 C., is prepared from 4-[5(3)-methyl-3(5)-pyrazolyl]pyridine and allyl chloride as described in Example 13, except thatthe reaction is carried out for 18 hours under reflux in methanol.

EXAMPLE 28 Preparation 0) 1-methyl-4- [5 (3 -cyclopr0pyl-3 (5 pyrazolyl]pyridiniam chloride This compound, colorless crystals, melting point259- 261 C., is prepared from 4-[5(3)-cyclopropyl-3(5)1pyrazolyl]pyridine and methyl chloride as described in Example 13,except that the reaction is carried out for 18 hours in a bomb at C.with excess methyl chloride as solvent.

EXAMPLE 29 Preparation of 1-methyl-4-[4-methyl-3 (5 )pyrazolyl]pyridinium iodide The compound, colorless crystals, melting point 213-214 C., is prepared from 4-[4-methyl-3(5)-pyrazolyl] pyridine and methyliodide following the procedure described in Example 13, except that thereaction is carried out for 2 hours under reflux in methanol.

EXAMPLE 30 Preparation of 1 ,3-dimethyl-4- [5 (3 -methyl-3 (5pyrazolyll-pyridinium chloride The above compound, colorless crystals,melting point 263 265' C., is prepared from3-methyl-4-[5(3)-methyl-3(5)-pyrazolyl]pyri-dine and methyl chloride asdescribed in Example 13, except that the reaction is carried out for 20hours in a bomb at 90 C. With excess methyl chloride as solvent.

EXAMPLE 31 Preparation 0 1-methylallyl-4- [5 (3 -methyl-3 (5) pyrazolyl]pyridinium chloride The compound, colorless crystals, melting point 229-230 C., is prepared from 4-[5(3)-methyl-3(5)-pyrazolyl]pyridine andmethallyl chloride following the procedure as described in Example 13,except that the reaction is carried out for 18 hours under reflux withexcess methallyl chloride as solvent.

EXAMPLE 32 Preparation of 1-cinnamyl-4- [5 (3 -methyl-3 (5 pyrazolyl]piyridinium chloride This compound, colorless crystals, melting point207- 208 C., is prepared by reacting 4-[5(3)-methyl-3(5)-pyrazolynpyridine and cinnamyl chloride and using the procedure asdescribed in Example 13, except that the reaction is carried out :for 18hours under reflux in ethanol.

EXAMPLE 33 Preparation of 1-(3-methyl-2-baten-1-yl)-4-[5(3)- methyl-3(5) -pyrazolyl] pyridinium chlOrid e The compound, colorless crystals,melting point 19 C., is prepared from4-[5(3)-rnethyl-3(5)-pyrazolyl]pyridine and 1-chloro-3-methyl-2-buteneas described in Example 13, except that the reaction is carried out for4 hours under reflux in n-propyl alcohol.

EXAMPLE 34 Preparation of J-(Z-batea-I-yl) -4-[5(3) methyl-3pyrazolyl]pyridinium chloride The above compound, colorless crystals,melting point 162-163 C., is prepared by reacting 4-[5(3)-methyl-3(5)-pyrazolyl]-pyridine and l-chloro-Z-butene using the proceduredescribed in Example 13, except that the reaction is carried out for 18hours under reflux in isopropyl alcohol.

1 EXAMPLE 35 Preparation of I-(Z-methoxyethyl) -4-[5 (3)-methyl-3 (5pyrazolyflpyridiniam chloride The compound, colorless crystals, meltingpoint 209- 210 C., is prepared from4-[5(3)-methyl-3(5)-pyrazolyl]pyridine and l-chloro-Zanethoxyethane asdescribed in Example 13, except that the reaction is carried out for 18hours under reflux in n-p-ropyl alcohol.

EXAMPLE 36 Preparation of 1-cycl0pr0pylmethyl-4-[5 (3)-methyl-3 (5pyrazolyflpyridiniwm bromide The above compound, colorless crystals,melting point 22022l C., is prepared from 4-[5(3)-methy1-3 (5)-pyrazolyl] pyridine and cyclopropylmethyl bromide as described inExample 13, except that the reaction is carried out for 18 hours at 90C. in toluene.

EXAMPLE 37 Hard gelatin capsules Gm. 1 methy1-4- [5 (3 -ethyl-3 (5-p-yrazolyl] pyridinium chloride 100 Cornstarch 75 Magnesium stearate,powder 25 Talc 25 The finely powdered ingredients are mixed thoroughlyand then encapsulated in 1000 two-piece hard gelatin capsules eachcontaining 100 mgs. of 1-methyl-4-[5(3)- ethyl-3 (5 -pyrazolyl]pyridinium chloride.

EXAMPLE 38 Soft gelatin capsules One piece soft gelatin capsules fororal use each containing 150 mgs. of1-methyl-4-[5(3)-ethyl-3(5)-pyrazolyl]pyridinium iodide are prepared byfirst dispersing the compound in sufiicient corn oil to render thematerial capsulatable and then encapsulating in the usual manner.

pyrazolyl]pyridinium bromide are prepared from the followingingredients:

1- n butyl 4 [5(3) methyl 3(5) pyrazolylJ-pyridinium bromide 1000Lactose 1500 Magnesium stearate 500 Talc 500 formula:

1 A N R2 R l 6 \llg/ I R: X

wherein R is selected from the group consisting of hydrogen, lower alkyland cyclopropyl; R and R are selected from the group consisting ofhydrogen and lower alkyl; R is selected from the group consisting oflower alkyl, lower alkenyl, cinnamyl, cyclopropylmethyl and loweralkoxy-(lower) alkyl; X is a pharmaceutically acceptable anion and asolid edible carrier.

2. A therapeutic composition in accordance with claim 1 wherein thepyrazolylpyridinium salt is l-methyl-4- [5 3 -ethyl-3 (5 -pyrazolyl]pyridinium chloride.

3. A therapeutic composition in accordance with claim 1 wherein thepyrazolylpyridinium salt is 1-methyl-4- [5 (3 -ethyl-3 5 -pyrazolyl]pyridinium iodide.

4. A therapeutic composition in accordance with claim 1 wherein thepyrazolylpyridinium salt is 1-methyl-4- [5 (3 methyl-3 (5 -pyrazolyl]pyridinium chloride.

5. A therapeutic composition in accordance with claim 1 wherein thepyrazolylpyridinium salt is l-n-butyl- 4- [5 (3 )-methyl-3 5 -pyrazolyl]pyridinium bromide.

6. A therapeutic composition in accordance with claim 1 wherein thepyrazolylpyridinium salt is 1-n-butyl-4- [5 (3 -methyl-3 (5 -pyrazolyl]pyridinium chloride.

7. A therapeutic composition in accordance with claim 1 wherein thepyrazolylpyridinium salt is 1-methyl-4- [3 (5 -pyrazolyl] pyridiniumchloride.

8. A therapeutic composition in accordance with claim 1 wherein thepyrazolylpyridinium salt is 1,3-dimethyl- 4- [5 (3 -methyl-3 (5-pyrazolyl] pyridinium chloride.

9. A therapeutic composition in accordance with claim 1 wherein thepyrazolylpyridinium salt is 1-(3- methyl-2-buten-1-yl)-4-[5(3)-methyl3(5) pyrazolyl]- pyridinium chloride.

10. A therapeutic composition in accordance with claim 1 wherein thepyrazolylpyridinium salt is 1-(2- buten 1 yl) 4 [5(3) methyl 3(5)pyrazolyl] pyridinium chloride.

11. The method of inducing hypoglycemia which comprises administeringorally to a warm-blooded animal in whom a hypoglycemic elfect is desiredan amount sufficient to produce hypoglycemia of a pyrazolylpyridiniumsalt of the formula:

wherein R is selected from the group consisting of hydrogen, lower alkyland cyclopropyl; R and R are selected from the group consisting ofhydrogen and lower alkyl; R is selected from the group consisting oflower alkyl, lower alkenyl, cinnamyl, cyclopropylmethyl and loweralkoxy-(lower)alkyl; and X is a pharmaceutically acceptable anion.

12. The method of inducing hypoglycemia which comprises administeringorally to a warm-blooded animal in whom a hypoglycemic effect is desireda sufficient amount of 1 1 methyl 4-[5(3)-ethyl-3()-pyrazolyl]pyridinium chloride.

13. The method of inducing hypoglycemia which comprises administeringorally to a warm-blooded animal in whom a hypoglycemic effect is desireda sufiicient amount of 1 methyl 4 [5(3) ethyl 3(5) pyrazolyl] pyridiniumiodide.

14. The method of inducing hypoglycemia which comprises administeringorally to a warm-blooded animal in whom a hypoglycemic effect is desireda suflicient amount of 1 methyl 4 [5(3) methyl 3(5) pyrazolyl]pyridinium chloride.

15. The method of inducing hypoglycemia which comprises administeringorally to a warm-blooded animal in whom a hypoglycemic effect is desireda sufiicient amount of 1- n butyl 4 [5(3) methyl 3(5) pyrazolyl]pyridinium bromide.

16. The method of inducing hypoglycemia which comprises administeringorally to a warm-blooded animal in whom a hypoglycemic effect is desireda sufficient amount of 1 n butyl 4 [5(3) methyl 3(5) pyrazolyl]pyridinium chloride.

17. The method of inducing hypoglycemia which comprises administeringorally to a warm-blooded animal in whom a hypoglycemic effect is desireda sufiicient amount of 1 methyl 4 [3(5) pyrazolyl1pyridinium chloride.

18. The method of inducing hypoglycemia which comprises administeringorally to a warm-blooded animal in whom a hypoglycemic efiect is desireda sufficient amount of 1,3 dimethyl 4 [5(3) methyl 3(5) pyrazolyl]pyridinum chloride.

19. The method of inducing hypoglycemia which comprises administeringorally to a warm-blooded animal in whom a hypoglycemic effect is desireda sufficient amount of 1- (3 methyl 2 buten 1 yl) 4 [5(3)- methyl-3 (5-pyrazolyl] -pyridinium chloride.

20. The method of inducing hypoglycemia which comprises administeringorally to a warm-blooded animal in whom a hypoglycemic effect is desireda sufficient amount of 1- (2 buten l yl) 4 [5(3) methyl 3(5)-pyrazolyl]pyridinium chloride.

References Cited UNITED STATES PATENTS 3,150,148 9/1964 Dulin 167--653,190,888 6/1965 Wolf 167-65 ALBERT T. MEYERS, Primary Examiner. JEROMED. GOLDBERG, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,341,413 September 12, 1967 Edward Charles Tocus et a1.

It is hereby certified that error appears in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

Columns 3 and 4, in the TABLE, second column, line 18 thereof, for "270"read 250 same TABLE, third column, line 18 thereof, for "88" read 66same TABLE, sixth column, line 12 thereof, for "35:8" read 36:8 column 7line 30 for "pyraXo1-" in italics, read pyrazolin italics;

column 10, lines 16 to 21, for that portion of the formula reading I R2read R3 Signed and sealed this 1st day of October 1968. (SEAL) Attest:

EDWARD J. BRENNER Commissioner of Patents Edward M. Fletcher, Jr.

Attesting Officer

11. THE METHOD OF INDUCING HYPOGLYCEMIA WHICH COMPRISES ADMINISTERINGORALLY TO A WARM-BLOODED ANIMAL IN WHOM A HYPOGLYCEMIC EFFECT IS DESIREDAN AMOUNT SUFFICIENT TO PRODUCE HYPOGLYCEMIA OF A PYRAZOLYLPYRIDINIUMSALT OF THE FORMULA: